A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After Programmed Cell Death Protein 1 (PD1) Blockade

• ClinicalTrials.gov Identifier: NCT03003676
• Recruitment Status: Active, not recruiting
• First Posted: December 28, 2016
• Last Update Posted: October 8, 2020
• Sponsor: Targovax Oy
• Information provided by (Responsible Party): Targovax ASA ( Targovax Oy )

Tracking Information

• First Submitted Date: December 19, 2016
• First Posted Date: December 28, 2016
• Last Update Posted Date: October 8, 2020
• Study Start Date: December 2016
• Actual Primary Completion Date: July 2020 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: April 11, 2019): Incidence of treatment-emergent adverse events including treatment-emergent serious adverse events assessed by CTCAE. [ Time Frame: 6 months ]
• Original Primary Outcome Measures (submitted: December 21, 2016): Safety of sequential treatment with ONCOS-102 followed by pembrolizumab by assessment of laboratory parameters (routine haematology and biochemistry), vital signs and recording of adverse events. [ Time Frame: 6 months ]

Current Secondary Outcome Measures (submitted: December 21, 2016)

• Objective response rates by RECIST 1.1 and irRECIST. [ Time Frame: 6 months ]
• Changes in immune cell subsets in tumor tissue before and after ONCOS-102 and pembrolizumab. [ Time Frame: 6 months ]
• Changes in immune cell subsets in peripheral blood before and after ONCOS-102 and pembrolizumab. [ Time Frame: 6 months ]
• Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR). [ Time Frame: 6 months ]
• Progression Free Survival (PFS) assessed by RECIST 1.1 and irRECIST. [ Time Frame: 6 months ]
• Clinical benefit rate, defined as any confirmed objective response by RECIST 1.1 or stable disease. [ Time Frame: 6 months ]
• Clinical benefit rate, defined as any objective response by irRECIST criteria or immune-related stable disease. [ Time Frame: 6 months ]
• Change in size in individual lesions. [ Time Frame: 6 months ]

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: December 21, 2016)

• Somatic mutational rate and neoepitope burden in tumors and explore relationship to response. [ Time Frame: 6 months ]
• Changes in T cell receptor clonality in infiltrating and circulating T cells. [ Time Frame: 6 months ]
• Gene expression changes in the tumor microenvironment and peripheral blood. [ Time Frame: 6 months ]

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After Programmed Cell Death Protein 1 (PD1) Blockade
• Official Title: A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After PD1 Blockade
• Brief Summary: This is a multi center, phase I pilot study of sequential ONCOS-102 and pembrolizumab in patients with advanced or unresectable melanoma progressing after PD1 blockade. The primary objective of the study is to determine the safety of sequential treatment with ONCOS-102 followed by pembrolizumab. The protocol aims to enroll patients into two cohorts: Part I: up to 12 patients will receive sequential treatment with ONCOS-102 followed by pembrolizumab. Part II: up to 12 patients will receive an initial treatment phase with ONCOS-102 followed by a treatment phase with ONCOS-102 in combination with pembrolizumab.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced or Unresectable Melanoma Progressing After PD1 Blockade

Intervention

• Biological: ONCOS-102
  Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)
• Drug: Cyclophosphamide
  Pre-treatment
• Drug: Pembrolizumab
  PD1 blockade

Study Arms

Experimental: Experimental: ONCOS-102+cyclophosphamide+pembrolizumab

Part I: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24).

Part II: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).

Interventions:

• Biological: ONCOS-102
• Drug: Cyclophosphamide
• Drug: Pembrolizumab

• Publications *: Kuryk L, Møller AW, Jaderberg M. Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model. Oncoimmunology. 2018 Oct 29;8(2):e1532763. doi: 10.1080/2162402X.2018.1532763. eCollection 2019.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 16, 2020): 21
• Original Estimated Enrollment (submitted: December 21, 2016): 12
• Study Completion Date: Not Provided
• Actual Primary Completion Date: July 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adults 18 years of age or older.
• For US sites: Histopathologically confirmed melanoma with an injectable cutaneous or lymph node metastasis that has progressed in the opinion of the treating investigator despite administering a Food and Drug Administration (FDA) approved anti-PD1 agent, with or without ipilimumab.
• For European sites: Histopathologically confirmed melanoma with an injectable cutaneous or lymph node metastasis that has progressed in the opinion of the treating investigator despite administering a regulatory approved anti-PD1 agent, with or without ipilimumab.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
• Measurable disease according to RECIST 1.1.
• Acceptable coagulation status: international normalised ratio (INR) of blood clotting, prothrombin time and activated partial thromboplastin time within ≤1.5 x upper limit of normal (ULN).
• Completion of local therapy, such as radiation, surgical resection, injectable immunebased therapy, or topical pro-inflammatory agent, 21 days prior to first dose of protocol therapy.
• Adverse events from previous cancer therapies (excluding alopecia) must have recovered to grade 1 (CTCAE, most recent version). Stable grade 2 AEs such as endocrine conditions are allowed, and other chronic stable AEs may be considered on a case by case basis by the Principal Investigator.
• Clinical stability of brain metastases for at least 4 weeks prior to first day of study therapy.

• Acceptable liver and renal functions defined as:

  • Total bilirubin ≤1.5 x ULN (does not include patients with Gilbert's Disease)
  • Aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) ≤3.0 x ULN
  • Serum creatinine ≤1.5 x ULN

• Acceptable haematological function defined as (Patients can be transfused to meet the haemoglobin entry criteria):

  • Haemoglobin ≥9 g/dL
  • Neutrophils ≥1.5 x 10^9/L
  • Platelet count ≥75 x 10^9/L
• Able to provide valid written informed consent.
• All women of childbearing potential must have a negative urine or serum pregnancy test at screening.
• For US sites: All patients must agree to use barrier contraception (i.e. condom) during study treatment and for 2 months after the last virus treatment and 4 months after the last dose of chemotherapy and pembrolizumab.
• For European sites: All patients must agree to use highly effective contraception for at least 6 months (according to the latest country specific SmPC) after administration of CPO, up to 4 months after last dose of pembrolizumab, and up to 2 months after last dose of ONCOS-102, whichever comes last.
• For European sites: All women of child-bearing potential must agree to perform pregnancy testing throughout the study starting at baseline, every 3 weeks from day 22 until last dose of study medication (ONCOS-102 and pembrolizumab) and then every month for at least 6 months.

Exclusion Criteria:

• A concomitant medical condition requiring receipt of a therapeutic anticoagulant that in the opinion of the treating physician cannot safely allow for therapeutic injection of ONCOS-102 and tumor biopsies. Local clinical practice can be followed with regard to holding a therapeutic anticoagulant during invasive procedures such as biopsies.
• A concomitant medical condition that in the opinion of the treating physician would pose unreasonable additional risk to therapeutic injection of ONCOS-102.
• For US sites: Receipt of Investigational agents within 28 days prior to first dose of protocol therapy.
• For European sites: Current participation or participation in a study of an investigational agent within 28 days prior to first dose of protocol therapy. Note: participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Any symptomatic autoimmune disease (such as lupus, scleroderma, Crohn's disease, ulcerative colitis) that requires administration of >10mg of prednisone equivalent. Lower dose steroids for conditions such as hypophysitis are allowed.

• Any prior severe adverse event attributed to prior anti-PD1 therapy that, in the Principal investigator's opinion, would contraindicate pembrolizumab administration such as:

  • Grade 2 or higher pneumonitis
  • Grade 4 AST or ALT elevation
  • Grade 3 or higher colitis attributable to PD1 blockade; note that colitis attributable to ipilimumab is not excluded
  • Note: in the absence of clinical symptoms of pancreatitis, elevations of amylase or lipase are not contraindications to therapy on this trial
• Known active infection with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or HIV. Cleared HBV/HCV infection is not an exclusion, nor is HIV infection with cluster of differentiations 4 (CD4) counts >500 and an undetectable viral load.
• Active bacterial, viral, or fungal infections, requiring systemic therapy apart from anti-viral maintenance therapy for HIV.
• History of organ transplant.
• Patients requiring chronic systemic immunosuppressants, including steroids (prednisone daily equivalent of >10 mg).
• Brain metastases that are clinically unstable (e.g. showing unequivocal growth on imaging, requiring radiation therapy, or steroids >10mg of prednisone equivalent) within 4 weeks of first dose of study drug.
• Known severe congenital or acquired cellular or humoral immunodeficiency such as common variable immunodeficiency.
• For US sites: Women who are pregnant or breast-feeding currently or are planning to conceive during or up to 4 months after end of protocol therapy.
• For European sites: Women who are currently pregnant or breast-feeding or are planning to conceive during or up to 6 months after end of protocol therapy.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway, United States

Administrative Information

• NCT Number: NCT03003676
• Other Study ID Numbers: ONCOS C824
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Targovax ASA ( Targovax Oy )
• Study Sponsor: Targovax Oy
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Targovax ASA
• Verification Date: October 2020